Wound gel containing antimicrobial composition

ABSTRACT

A gel useful in reducing bacterial colonization in or around the area of a wound includes at least one PEG and an aqueous composition having a pH of from 2 to 4, a total solute concentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7 g/L of at least one cationic surfactant. The aqueous composition can include a buffer system that includes an organic acid and a salt of an organic acid. The gel is effective even when free of materials having antimicrobial properties other than those provided by the aqueous composition such as sporicides, antifungals and antibiotics.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/075,147, filed 19 Mar. 2016 and presently pending, which is acontinuation of U.S. patent application Ser. No. 13/684,456, filed 23Nov. 2012 and now issued as U.S. Pat. No. 9,314,017, which is acontinuation of international appl. no. PCT/US2012/059263, filed 8 Oct.2012, which claims the benefit of U.S. patent appl. No. 61/545,108,filed 8 Oct. 2011, and 61/660,649, filed 15 Jun. 2012, the disclosuresof all of which are incorporated herein by reference.

BACKGROUND INFORMATION

Microbes are found virtually everywhere, often in high concentrations,and are responsible for a significant amount of disease and infection.Killing and/or eliminating these microorganisms is desirable for avariety of reasons.

Bacteria present special challenges because they can exist in a numberof forms (e.g., planktonic, spore and biofilm) and their selfpreservation mechanisms make them extremely difficult to treat and/oreradicate. For example, the bacteria in biofilms or spores aredown-regulated (sessile) and not actively dividing, which makes themresistant to attack by a large group of antibiotics and antimicrobialsthat attack the bacteria during the active parts of their lifecycle,e.g., cell division.

In a biofilm, bacteria interact with and adhere to surfaces and formcolonies which facilitate continued growth. The bacteria produceexopolysaccharide (EPS) and/or extracellular-polysaccharide (ECPS)macromolecules that keep them attached to the surface and form aprotective barrier effective against many forms of attack. Protectionmost likely can be attributed to the small diameter of the flow channelsin the matrix, which restricts the size of molecules that can reach theunderlying bacteria, and consumption of biocides through interactionswith portions of the EPS/ECPS macromolecular matrix and bacterialsecretions and waste products contained therein. (Certain fungi also canform biofilms, many of which present the same types of challengespresented here.)

Bacteria also can form spores, which are hard, non-permeableprotein/polysaccharide shells or coatings. Spores provide additionalresistance to eradication efforts by preventing attack from materialsthat are harmful to the bacteria.

Due to the protection afforded by a macromolecular matrix (biofilm) orshell (spore) and their down-regulated state, bacteria in these statesare very difficult to treat. The types of biocides and antimicrobialseffective in treating bacteria in this form are strongly acidic and/oroxidizing, often involving halogen atoms, oxygen atoms, or both. Commonexamples include hypochlorite solutions (e.g., bleach), phenolics,mineral acids (e.g., HCl), H₂O₂, and the like. Large dosages of suchchemicals must be allowed to contact the biofilm or spore for extendedamounts of time to be effective, which makes them impractical for manyapplications.

Recently developed formulations intended for use in connection withcompromised animal/human tissue solvate a biofilm matrix so thatstill-living bacteria can be rinsed or otherwise removed from infectedtissue; see, e.g., U.S. Pat. Nos. 7,976,873, 7,976,875, 7,993,675, etc.The concentrations of active ingredients in these formulations are toolow to effectively kill the bacteria, however, thus making suchformulations ill suited for use as surface disinfectants.

Neutral-to-very acidic disinfecting solutions that can disruptmacromolecular matrices, or bypass and/or disable their inherentdefenses, allowing ingredients in the solutions to access the bacteria,attack cell membranes, and kill them have been described in U.S. Pat.Publ. No. 2010/0086576 A1.

Animal tissue wounds present both a good environment for bacterial, andeven biofilm, growth and a surface or substrate requiring gentletreatment, thus making a difficult problem even worse.

Dental plaque, a biofilm that adheres to a tooth surface, consists ofbacterial cells (mainly Streptococcus mutans and Streptococcus sanguis),salivary polymers and bacterial extracellular products. The accumulationof microorganisms subject the teeth and gingival tissues to highconcentrations of bacterial metabolites, which results in widespreadproblems such as gingivitis and periodontal disease, including oralcaries.

Nosocomial or hospital acquired infections (HAIs) can be caused byviral, bacterial, and/or fungal pathogens and can involve any system ofthe body. HAIs are a leading cause of patient deaths, and they increasethe length of hospitalizations for patients, mortality and healthcarecosts; in the developed world, they are estimated to occur in 5-10% ofall hospitalizations, even higher for pediatric and neonatal patients.They often are associated with medical devices or blood producttransfusions. Three major sites of HAIs are bloodstream, respiratorytract, and urinary tract. Most patients who have HAIs have invasivesupportive measures such as central intravenous lines, mechanicalventilation, and catheters, which provide an ingress point forpathogenic organisms. Ventilator-associated pneumonia can be caused byStaphylococcus aureus, methicillin-resistant Staphylococcus aureus(MRSA), Candida albicans, Pseudomonas aeruginosa, Acinetobacterbaumannii, Stenotrophomonas maltophilia, Clostridium difficile, andTuberculosis, while other HAIs include urinary tract infections,pneumonia, gastroenteritis, vancomycin-resistant Enterococcus (VRE), andLegionellosis.

Medical equipment such as endoscopes, gastroscopes, the flow-channels ofhematology and dialyzer equipment, the airflow path of respiratoryequipment, ISE, HPLC, and certain catheters are designed to be usedmultiple times. Significant risks have been associated with inadequateor improper cleaning due to the presence of residual soil and/orimproper disinfection or sterilization, up to and including HAIs fromcontaminated devices such as bronchoscopes contaminated withMycobacterium tuberculosis and the transmission of Hepatitis C virus topatients during colonoscopy procedures.

Any surface that is or becomes moist is subject to biofilm formation.Thus, articles intended for permanent or temporary implantation—such asartificial hearts, stents, contact lenses, intrauterine devices,artificial joints, dental implants—are particularly susceptible. Extrememeasures are taken to prevent biofilm formation because, onceestablished, they are essentially impossible to eradicate in vivo andcan cause life-altering, even lethal, infections.

Compositions and articles that can be used in the treatment of microbessuch as bacteria remain desirable. Liquids that break down the EPS/EPCSmacromolecular matrix or that bypass and/or disable the defensesinherent in therein, thereby permitting the liquid or a componentthereof to access and kill the bacteria in a down-regulated state, areparticularly desirable. Such a liquid that is lethally effective whilehaving no or very limited toxicity is of significant interest andcommercial value.

Methods and articles capable of treating bacteria that colonize acutewounds at the time of injury and during all stages of healing, as wellas in the treatment of chronic wounds, also are highly desirable.

Also of significant interest are methods, compositions capable oftreating and/or remedying any of a variety of oral and mucosalconditions associated with biofilms; preventing or remedying HAIs and/orbiofilms in which the microorganisms can be entrained; preventing thegrowth of or removing biofilms from implantable (or implanted) devicesand articles; and sterilizing or otherwise processing multiuse medicalequipment.

SUMMARY

The present invention is directed to compositions and articles that canbe used in treatment or elimination of microbes including but notlimited to bacteria, regardless of whether they are in planktonic,spore, or biofilm form.

An aqueous composition according to the present invention is lethaltoward a wide spectrum of gram positive and gram negative bacteria andexhibits lethality toward other microbes such as viruses, fungi, molds,yeasts, and bacterial spores.

In addition to having a pH greater than 7, the composition includes asignificant amount of one or more surfactants and large amounts ofosmotically active solutes. The composition is effective at interruptingor breaking ionic crosslinks in the macromolecular matrix of a biofilm,which facilitates passage of the solutes and surfactant through thematrix to the bacteria entrained therein and/or protected thereby. Theseingredients, while typically ineffective against bacteria when used inisolation or at low concentrations, become very effective at breakingdown the bacterial biofilm or bypassing and disabling the bacterialbiofilm defenses, allowing the bacteria in its several states to beaccessed and killed (by inducing membrane leakage in bacteria, leadingto cell lysis) when provided in the correct combination and insufficient concentrations.

Articles, compositions and methods for treating wound areas also areprovided. Non-solid compositions can be applied to the area; thecomposition can be non-flowing if it is intended to be left in place orcan be a liquid if it is intended to irrigate or otherwise flow over oraround a treatment area. A solid article can be applied to a woundtreatment area; such an article can be adapted to be left in place on ornear the treatment area or can be intended for temporary application andremoval. An antihemorrhagic can be included in a composition or articleto permit the composition or article to stanch bleeding, in addition toproviding antimicrobial treatment. These aspects also provide methods ofcleaning, dressing and otherwise treating wounds.

Also provided are articles, compositions, and methods for protectingagainst or treating microbial attack of the mouth, teeth, gums, lips,oral mucosal lining, particularly attack by biofilm-related conditionsincluding, but not limited to, oral caries, gingivitis, periodontitis,halitosis, and peri-implantitis.

Further, HAIs can be prevented or remedied by applying a liquid or solidantimicrobial composition to a surface located in a medical treatmentfacility so as to prevent or remove a biofilm and/or kill bacterialentrained therein. A patient possessing a HAI also can be treated withan antimicrobial composition or an article including or based thereon.

Additionally, the surfaces of permanently or removably implantableobjects can be treated so as to prevent biofilm formation or, afterimplantation, can be treated to remove biofilm on such surfaces.

Reusable medical equipment also can be processed so as to removeEPS/ECPS, materials conducive to the growth of EPS/ECPS, and organismsthat are or can be entrained in EPS/ECPS. The processing can involvesterilization or can supplement existing sterilization techniques andresults in medical equipment that is less likely to introduce microbes,particularly bacteria, into a patient treated therewith.

To assist in understanding the following description of variousembodiments, certain definitions are provided immediately below. Theseare intended to apply throughout unless the surrounding text explicitlyindicates a contrary intention:

-   -   “microbe” means any type of microorganism including, but not        limited to, bacteria, viruses, fungi, viroids, prions, and the        like;    -   “antimicrobial agent” means a substance having the ability to        cause greater than a 90% (1 log) reduction in the number of one        or more of microbes;    -   “active antimicrobial agent” means an antimicrobial agent that        is effective only or primarily during the active parts of the        lifecycle, e.g., cell division, of a microbe;    -   “biofilm” means a community of microbes, particularly bacteria        and fungi, attached to a surface with the community members        being contained in and/or protected by a self-generated        macromolecular matrix;    -   “residence time” means the amount of time that an antimicrobial        agent is allowed to contact a bacterial biofilm;    -   “biocompatible” means presenting no significant, long-term        deleterious effects on or in a mammalian species;    -   “biodegradation” means transformation, via enzymatic, chemical        or physical in vivo processes, of a chemical into smaller        chemical species;    -   “antihemorrhagic” means a compound or material that inhibits        bleeding by any one or more of inhibiting fibrinolysis,        promoting coagulation, promoting platelet aggregation, or        causing vasoconstriction;    -   “hospital acquired infection” means a localized or systemic        infection not present, and without evidence of incubation, at        the time that a patient is admitted to a health care setting,        most of which become clinically evident within 48 hours of        admission;    -   “polyelectrolyte” means a polymer with multiple mer that include        an electrolyte group capable of dissociation in water;    -   “strong polyelectrolyte” is a polyelectrolyte whose electrolyte        groups completely dissociate in water at 3≦pH≦9;    -   “weak polyelectrolyte” is a polyelectrolyte having a        dissociation constant of from ˜2 to ˜10, i.e., partially        dissociated at a pH in the range where a strong        polyelectrolyte's groups are completely dissociated; and    -   “polyampholyte” is a polyelectrolyte with some mer including        cationic electrolyte groups and other mer including anionic        electrolyte groups.

Hereinthroughout, pH values are those which can be obtained from any ofa variety of potentiometric techniques employing a properly calibratedelectrode.

The relevant portions of any specifically referenced patent and/orpublished patent application are incorporated herein by reference.

DETAILED DESCRIPTION

Useful basic (caustic) liquid compositions display at least moderatelyhigh tonicity, i.e., large amounts of osmotically active solutes and apH that is relatively high (7.5≦pH≦9) or even very high (9≦pH≦11). Thelarge amount of solutes work with surfactants that are present to inducemembrane leakage in bacteria, leading to cell lysis.

The composition can contain as few as three ingredients: water, thedissociation product(s) of at least one base, and at least onesurfactant, each of which generally is considered to be biocompatible.The dissociation product(s) of one or more salts also can be included.

Reductions in the concentration of hydronium ions, i.e., increases inpH, generally correspond with enhanced efficacy. This effect may not belinear, i.e., the enhancement in efficacy may be asymptotic below acertain hydronium ion concentration. As long as the pH of thecomposition is greater than 7 and less than −10, the basic compositiongenerally will be considered to be biocompatible; specifically, externalexposure will result in no long-term negative dermal effects.

Basicity is achieved by adding to water (or vice versa) one or morebases such as, but not limited to, alkali metal salts of weak acidsincluding acetates, fulmates, lactates, phosphates, and glutamates;alkali metal nitrates; alkali metal hydroxides, in particular NaOH andKOH; alkali earth metal hydroxides, in particular Mg(OH)₂; alkali metalborates; NH₃; and alkali metal hypochlorites (e.g., NaClO) andbicarbonates (e.g., NaHCO₃).

In certain embodiments, preference can be given to those organiccompounds which are, or can be made to be, highly soluble in water. Inthese and/or other embodiments, preference can be given to those baseswhich are biocompatible. Alternatively or additionally, preference canbe given to those organic acids and bases which can act to chelate themetallic cations ionic involved in crosslinking the macromolecularmatrix of a biofilm.

Surfactant can be added to water before, after or at the same time asthe base(s). Essentially any material having surface active propertiesin water can be employed, although those that bear some type of ioniccharge are expected to have enhanced antimicrobial efficacy because suchcharges, when brought into contact with a bacteria, are believed to leadto more effective cell membrane disruption and, ultimately, to cellleakage and lysis. This type of antimicrobial process can kill evensessile bacteria because it does not involve or entail disruption of acellular process. Potentially useful anionic surfactants include, butare not limited to, sodium chenodeoxycholate, N-lauroylsarcosine sodiumsalt, lithium dodecyl sulfate, 1-octanesulfonic acid sodium salt, sodiumcholate hydrate, sodium deoxycholate, sodium dodecyl sulfate, sodiumglycodeoxycholate, sodium lauryl sulfate, and the alkyl phosphates setforth in U.S. Pat. No. 6,610,314. Potentially useful cationicsurfactants include, but are not limited to, cetylpyridinium chloride,tetradecyltrimethylammonium borime, benzalkonium chloride,hexadecylpyridinium chloride monohydrate and hexadecyltrimethylammoniumbromide, with the latter being a preferred material. Potentially usefulnonionic surfactants include, but are not limited to,polyoxyethyleneglycol dodecyl ether, N-decanoyl-N-methylglucamine,digitonin, n-dodecyl B-D-maltoside, octyl B-D-glucopyranoside,octylphenol ethoxylate, polyoxyethylene (8) isooctyl phenyl ether,polyoxyethylene sorbitan monolaurate, and polyoxyethylene (20) sorbitanmonooleate. Useful zwitterionic surfactants include but are not limitedto 3-[(3-cholamidopropyl) dimethylammonio]-2-hydroxy-1-propanesulfonate, 3-[(3-cholamidopropyl) dimethylammonio]-1-propane sulfonate,3-(decyldimethylammonio) propanesulfonate inner salt, andN-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate. For otherpotentially useful materials, the interested reader is directed to anyof a variety of other sources including, for example, U.S. Pat. Nos.4,107,328, 6,953,772, and 7,959,943. Particular classes and types ofsurfactants can be preferred for certain end use applications, with someof these being specifically referenced later in this document.

The composition contains a sufficient amount of surfactant to interruptor rupture bacterial cell walls. The amount of surfactant constitutesgreater than ˜0.075%, ˜0.10%, ˜0.125%, ˜0.15% or 0.175%, generally atleast ˜0.2%, typically at least ˜0.5%, more typically at least ˜0.7%,often at least ˜0.9%, and preferably at least 1% of the composition (allbeing weight percentages based on total weight of the composition), withthe upper limit being defined by the solubility limits of the particularsurfactant(s) chosen. Some surfactants can permit extremely high loadinglevels, e.g., at least 5%, at least 10%, at least 12%, at least 15%, atleast 17%, at least 20%, or even on the order of ˜25% or more (again,all being weight percentages based on total weight of the composition).Any of the foregoing minimum amounts can be combined with any of theforegoing maximum amounts to provide an exemplary range of potentialamounts of surfactant.

Ionically charged compounds that do not qualify as a surfactants mightbe able to replace some or all of the surfactant component in someinstances. Ionically charged compounds include natural polymers such aschitosan and glucosides, as well as charged molecules and atoms such assuch as Cl⁻, Na⁺, NH₄ ⁺, HCO₃ ⁻, SO₄ ⁻², HSO₄ ⁻, S₂O₃ ⁻², SO₃ ⁻², OH⁻,NO₃ ⁻, ClO₄ ⁻, CrO₄ ⁻², Cr₂O₇ ⁻², MnO₄ ⁻², PO₄ ⁻³, HPO₄ ⁻², H₂PO₄ ⁻, andthe like. These types of ions also can increase the osmolarity of acomposition without increasing its pH past a desired target; see also,e.g., U.S. Pat. No. 7,090,882. Such compounds, upon dissociation,increase the effective amount of solutes in the composition withoutgreatly impacting the molar concentration of hydroxyl ions while, insome cases, simultaneously providing a buffer system in the composition.

The lethality of the surfactant component(s) is increased and/orenhanced when the composition has at least moderate effective soluteconcentrations (tonicity). The osmolarity of the composition generallyincreases in proportion with the amount of base(s) employed, with theosmolarity maximum for a given composition primarily being a function ofthe solubility limits of the specific base(s). An obvious corollary toincreased levels of base(s) in the composition is lower concentrationsof hydronium ions, i.e., high pH values.

As noted previously, some end-use applications can call for acomposition with only a moderately high pH. To increase the osmolarityof a composition without increasing its pH past a desired target, one ormore types of other water soluble compounds can be included. Suchcompounds, upon dissociation, increase the effective amount of solutesin the composition without greatly impacting the molar concentration ofhydroxyl ions while, simultaneously, providing a buffer system in thecomposition. The ionically charged molecules and atoms discussed aboveare among those materials which can serve this function; see also, e.g.,U.S. Pat. No. 7,090,882.

Regardless of how achieved, the tonicity of the composition is at leastmoderately high, with an osmolarity of at least ˜0.3, ˜0.5, ˜0.7, ˜0.8,˜0.9 or ˜1 Osm/L being preferred for most applications. Depending onparticular end-use application, the composition can have any of thefollowing concentrations: at least ˜1.5 Osm/L, at least ˜1.75 Osm/L, atleast ˜2.0 Osm/L, at least ˜2.25 Osm/L, at least ˜2.5 Osm/L, at least˜2.75 Osm/L, at least ˜3.0 Osm/L, at least ˜3.25 Osm/L, at least ˜3.5Osm/L, at least ˜3.75 Osm/L, at least ˜4.0 Osm/L, and even at least˜4.25 Osm/L. Certain embodiments of the composition can exhibit soluteconcentrations of 0.3 to 5 Osm/L, 0.5 to 4.5 Osm/L, 0.75 to 4.4 Osm/L, 1to 4.3 Osm/L, 1.25 to 4.25 Osm/L, 1.4 to 4.1 Osm/L, and 1.5 to 4 Osm/L;other potentially useful ranges include 3 to 5 Osm/L, 2.5 to 4.5 Osm/L,3 to 4.5 Osm/L, 3.5 to 5 Osm/L, 3.25 to 4.5 Osm/L, and the like.

The composition can be employed in a variety of ways. For example, whenused to treat a biofilm on a surface (e.g., cutting board, counter,desk, etc.), the composition can be applied directly to the biofilm,optionally followed by physical rubbing or buffing, or the compositioncan be applied to the rubbing/buffing medium, e.g., cloth. Where abiofilm in an inaccessible area is to be treated, soaking or immersionof the biofilm in an excess of the composition can be performed for atime sufficient to essentially solvate the biofilm, which then can beflushed or wiped from the affected area. Regardless of contact method,the surfactant component(s) are believed to kill significant numbers ofbacteria without a need for the bacteria to be removed from the biofilmor vice versa.

Due to the abundance of microbial contamination, the composition mayfind utility in a large number of potential uses including, but notlimited to, household applications including non-compromised skin (hand,foot, hair, and body washing and/or deodorization), kitchen cleaning(countertop and surface cleaning, cleaning of food preparation utensils,dish washing, produce washing, etc.), bathroom cleaning (countertop andsurface cleaning, fixture cleaning, toilet bowl cleaning, sink and floordrain cleaning, and shower mildew eradication), laundry area cleaning(including laundry detergent, linen disinfection, and diapersterilization), baby sensitive applications such as cleaning and ordisinfecting baby contact products (including toys, bottles, pacifiers,nipples, teething rings, diapers, blankets, and clothing); commercialapplications include livestock care (facility and equipmentsterilization and dairy teat dip), produce sterilization (an alternativeto irradiation, which can be particularly useful against E. coli,listeria, salmonella, botulism, etc.), meat and poultry processingfacilities (including all surfaces, floors and drains, processingequipment and carcass washing), commercial kitchen and food preparationfacilities (countertop and surface cleaning, food preparation utensilcleaning, storage equipment and facilities cleaning, dish washing andproduce washing), mass food and beverage processing (processing andstorage equipment cleaning, tank sterilization, cleaning of liquidtransport lines, etc.), cleaning of water lines (e.g., for drinkingwater, beverage dispensers, dental offices, plumbing, heat exchangingsystems, and the like), and food and beverage transport (cleaning oftanker units for semi transport, cleaning of tanker cars for railroadtransport, and cleaning of pipelines); and non-traditional uses such asdenture cleaning, acne treatment, spermicides, laboratory equipmentcleaning, laboratory surface cleaning, oil pipeline cleaning, and testarticle processing for biofilm attachment.

The composition can be prepared in a number of ways. Description of anexemplary method follows.

Base (e.g., NaOH) and optional solute (e.g., a phosphate or sulfate) arecombined with sufficient water to constitute 60-90% of the calculateddesired volume. This solution can be stirred and/or heated. The desiredamount of surfactant(s) then can be added. Once stirring, if used, iscomplete, sufficient water is added so as to bring the composition tothe calculated tonicity and pH value. Advantageously, no specialconditions or containers are needed to store the composition for anextended time, although refrigeration can be used if desired.

A variety of additives and adjuvants can be included to make acomposition more amenable for use in a particular end-use applicationwithout negatively affecting its efficacy in a substantial manner.Examples include, but are not limited to, emollients, fungicides,fragrances, pigments, dyes, defoamers, foaming agents, flavors,abrasives, bleaching agents, preservatives (e.g., antioxidants) and thelike.

The composition does not require inclusion of an active antimicrobialagent for efficacy, but such materials can be included in certainembodiments. For example, one or more of bleach, any of a variety ofphenols, aldehydes, quaternary ammonium compounds, etc., can be added.

The composition conveniently can be provided as a solution, althoughother forms might be desirable for certain end-use applications.Accordingly, the composition can provided as a soluble powder (forsubsequent dilution, an option which can reduce transportation costs), aslurry, or a thicker form such as a gel or paste (which might beparticularly useful for providing increased residence times). For thelatter, the composition can include additional ingredients such as acoalescent (e.g., polyvinylpyrrolidone).

Embodiments of the composition can provide very large reductions in thenumber of bacteria, even with extremely short residence times. Forexample, a composition having high concentrations of surfactant (e.g.,1.5-2.5% by wt.) and total solutes (e.g., 2-4 Osm) can provide a 2, 3 or4 log (99.99%) reduction in the number of bacteria in an entrenchedbiofilm with a 3, 4, 5, 7, 8, 9, or 10 minute residence time and a 3, 4,5, or 6 log (99.9999%) reduction in the number of planktonic bacteriawith a mere 30-second residence time.

Quantitative Carrier Testing (ASTM E2197) is designed to determine thecontact time necessary to eradicate from a surface (e.g., countertops,sinks, bathroom fixtures, and the like) bacteria in a soil-loadedinoculum. In this test, bacteria combined with a soil loading and a 10μL inoculum is placed on a stainless steel carrier disk. After theinoculate is allowed to dry completely, 50 μL of antimicrobial treatmentcomposition is applied and allowed to stay in place for the desiredtreatment time, after which dilution with a saline dilution isperformed.

In addition to the foregoing general uses for the caustic composition ofthe present invention, certain specific end uses can employ the causticantimicrobial composition, its acidic counterpart or, in some instances,a solid antimicrobial material. The following paragraphs set forthinformation about an acidic antimicrobial composition and a solidantimicrobial material, as well as specific novel end uses for suchcompositions and materials.

Potentially useful acidic liquid compositions include those described inthe aforementioned U.S. Pat. Nos. 7,976,873, 7,976,875, and 7,993,675 aswell as U.S. Pat. Publ. No. 2010/0086576 A1, all of which include largeamounts of osmotically active solutes. A primary difference among theliquid compositions is pH, with those intended for use in the ear orsinus cavity being very moderate (e.g., commonly about 6≦pH≦7), whilethose intended for surface disinfection being more extreme, e.g.,relatively low (about 3≦pH≦6).

An acidic antimicrobial composition can contain as few as threeingredients: water, the dissociation product(s) of at least one acid,and at least one surfactant, each of which generally is considered to bebiocompatible. The dissociation product(s) of one or more alkali metalsalts of organic acids also can be included.

Increases in the concentration of hydronium ions, i.e., decreases in pH,generally correspond with enhanced efficacy and, again, the effect maynot be linear, i.e., the enhancement in efficacy may be asymptotic pasta certain hydronium ion concentration. As long as the pH of thecomposition is greater than ˜3, the composition generally will bebiocompatible; specifically, external exposure will result in nolong-term negative dermal effects.

Acidity is achieved by adding to water (or vice versa) one or moreacids, specifically strong (mineral) acids such as HCl, H₂SO₄, H₃PO₄,HNO₃, H₃BO₃, and the like or, preferably, organic acids, particularlyorganic polyacids. Examples of organic acids include monoprotic acidssuch as formic acid, acetic acid and substituted variants, propanoicacid and substituted variants (e.g., lactic acid, pyruvic acid, and thelike), any of a variety of benzoic acids (e.g., mandelic acid,chloromandelic acid, salicylic acid, and the like), glucuronic acid, andthe like; diprotic acids such as oxalic acid and substituted variants(including oxamic acid), butanedioic acid and substituted variants(e.g., malic acid, aspartic acid, tartaric acid, citramalic acid, andthe like), pentanedioic acid and substituted variants (e.g., glutamicacid, 2-ketoglutaric acid, and the like), hexanedioic acid andsubstituted variants (e.g., mucic acid), butenedioic acid (both cis andtrans isomers), iminodiacetic acid, phthalic acid, ketopimelic acid, andthe like; triprotic acids such as citric acid,2-methylpropane-1,2,3-tricarboxylic acid, benzenetricarboxylic acid,nitrilotriacetic acid, and the like; tetraprotic acids such as prehniticacid, pyromellitic acid, and the like; and even higher degree acids(e.g., penta-, hexa-, heptaprotic, etc.). Where a tri-, tetra-, orhigher acid is used, one or more of the carboxyl protons can be replacedby cationic atoms or groups (e.g., alkali metal ions), which can be thesame or different.

In certain embodiments, preference can be given to those organic acidswhich are, or can be made to be, highly soluble in water; acids thatinclude groups that enhance solubility in water (e.g., hydroxyl groups),examples of which include tartaric acid, citric acid, and citramalicacid, can be preferred in some circumstances. In these and/or otherembodiments, preference can be given to those organic acids which arebiocompatible; many of the organic acids listed above are used inpreparing or treating food products, personal care products, and thelike. Alternatively or additionally, preference can be given to thoseorganic acids which can act to chelate the metallic cations ionicinvolved in crosslinking the macromolecular matrix of a biofilm. This isdiscussed in more detail below.

Surfactant can be added to water before, after or at the same time asthe acid(s). As with the basic antimicrobial composition, thosesurfactants that bear some type of ionic charge are expected to yieldenhanced antimicrobial efficacy; such charges, when brought into contactwith a bacterium, are believed to lead to more effective cell membranedisruption and, ultimately, to cell leakage and lysis. Potentiallyuseful surfactants are the same as those described previously, withnon-ionic and cationic surfactants being at least somewhat preferredwhere the composition is intended for contact with dermal tissue.

The amounts of such surfactants that can be employed in the acidicantimicrobial composition are the same as those described above inconnection with the basic antimicrobial composition.

The lethality of the surfactant component(s) is increased and/orenhanced when the composition has at least moderate effective soluteconcentrations (tonicity). The osmolarity of the composition generallyincreases in proportion with the amount of acid(s) employed, with theosmolarity maximum for a given composition primarily being a function ofthe solubility limits of the specific acid(s). An obvious corollary toincreased levels of acid(s) in the composition is higher concentrationsof hydronium ions, i.e., low pH values. As noted previously, someend-use applications can call for a composition with only a moderatelylow pH. To increase the osmolarity of a composition without decreasingits pH past a desired target, one or more types of other water solublecompounds can be included. Such compounds, upon dissociation, increasethe effective amount of solutes in the composition without greatlyimpacting the molar concentration of hydronium ions while,simultaneously, providing a buffer system in the composition. Thematerials and methods for enhancing tonicity, as well as theosmolarities of the resulting compositions, are the same as thosedescribed above in connection with the basic antimicrobial composition.

Where one or more organic acids are used in the composition, tonicitycan be increased by including salt(s) of those acid(s) or other acid(s).For example, where the composition includes x moles of an acid, a manyfold excess (e.g., 3x-10x, preferably at least 5x or even at least 8x)of one or more salts of that base also can be included.

Both the basic and acidic antimicrobial liquid compositions have beendescribed primarily as solutions, although this is not limiting.Additional forms include emulsions, gels (including hydrogels,organogels and xerogels), pastes (i.e., suspension in an organic,typically fatty, base), salves or ointments, aerosols, foams, and evensuspensions.

Solid articles intended for use in disinfecting applications aredescribed in U.S. Pat. Publ. No. 2012/0288469. Solid materials include acrosslinked version of a water soluble polyelectrolyte and entrainedsurfactant. This combination of components permits the local chemistrywithin and immediately surrounding the solid material, when in use in anaqueous environment, to mimic that of the acidic versions of theaforedescribed liquid composition: high tonicity and high surfactantconcentration. The solid material can, but need not, include biocidaladditives, particularly active antimicrobial agents. When a liquid ispassed through or in proximity to the solid material, any bacteria orother microorganisms are exposed to the local chemistry conditionsdiscussed above: high tonicity, relatively low pH, and availablesurfactant, a combination that can induce membrane leakage in bacteria,leading to cell lysis. These characteristics permit the solid materialto be effective at bypassing and disabling bacterial biofilm and sporedefenses. In addition to being lethal toward a wide spectrum of grampositive and gram negative bacteria, the solid materials also canexhibit lethality toward other microbes such as viruses, fungi, molds,and yeasts.

The solid material requires some level of water or humidity to functioneffectively. This can determined or defined in a variety of ways. Thepolyelectrolytes must be capable of localized liquid charge interaction(meaning at least two water molecules are contacting or very near anelectrolyte group); alternatively, sufficient water must be present toactivate the charge of the electrolyte and/or to permit bacterialgrowth.

A solid antimicrobial material does not itself have a true pH. In use,however, the local pH of any aqueous composition in which it is deployedpreferably is lower than ˜7 to ensure proper antimicrobial activity.Reduced pH values (e.g., less than ˜6.5, ˜6.0, ˜5.5, ˜5.0, ˜4.5 and even˜4.0) generally are believed to correlate with increases in efficacy ofthe solid material, although this effect might be asymptotic for reasonsdescribed above.

In addition to more strongly acidic local environments, high localosmolarity conditions also are believed to increase efficacy.Accordingly, larger concentrations of polyelectrolytes, largerconcentrations of surfactant, surfactants with shorter chain lengths(e.g., no more than C₁₀, typically no more than C₈, commonly no morethan C₆), and surfactants with smaller side groups around the polargroup each are more desirable. (These factors also are applicable to thepreviously described liquid compositions.)

The lethality of the surfactant component(s) is increased and/orenhanced when the solid material can provide to the local environment inwhich it is deployed at least moderate effective solute concentrations,similar to that described above. Local osmolarity (tonicity) generallyincreases in proportion to the number and type of electrolytes presentin the polymeric network. (By local osmolarity is meant that of a liquidcontained in the solid material. While this might vary from place toplace throughout the article, preference is given to those solidmaterials capable of providing high local osmolarities throughout.)

The polyelectrolyte(s) that form the bulk of the solid materialpreferably are at least somewhat water soluble but also essentiallywater insoluble after being crosslinked. A partial list ofpolyelectrolytes having this combination of characteristics includes,but are not limited to, strong polyelectrolytes such as polysodiumstyrene sulfonate and weak polyelectrolytes such as polyacrylic acid,pectin, carrageenan, any of a variety of alginates,polyvinylpyrrolidone, carboxymethylchitosan, and carboxymethylcellulose.Included in potentially useful polyamphyolytes are amino acids andbetaine-type crosslinked networks; examples would be hydrogels based onsodium acrylate and trimethylmethacryloyloxyethylammonium iodide,2-hydroxyethylmethacrylate, or 1-vinyl-3(3-sulfopropyl)imidazoliumbetaine. Those polymeric materials having electrolyte groups thatcompletely (or nearly completely) dissociate in water and/or providerelatively low local pH values are desired for efficacy are preferred.Also preferred are those polyelectrolytes having a high density of merwith electrolyte-containing side groups.

Several crosslinking mechanisms including but not limited to chemical,high temperature self-crosslinking, and irradiation can be employed informing the solid material. Another option is to create crosslinksduring the polymerization process itself, such as by condensing adjacentsulfonic acid groups to yield sulfonyl crosslinks. Solid materials withhigher crosslink densities tend to maintain higher surfactantconcentrations for a longer period of time due to, presumably, longermean free paths in the polymeric network.

Independent of crosslinking method, the solid material can be formed bycrosslinking polymers (or polymerizable monomers) in an aqueous solutioncontained in a heat conductive mold, followed by rapid freezing andsubsequent lyophilizing. The resulting sponge-like material generallytakes the shape of the mold in which it was formed. Solids resultingfrom this type of process often have a spongy appearance, withrelatively large pores connected by tortuous paths. Often, pores lessthan ˜0.22 m, less than ˜0.45 m, less than ˜0.80 m, and less than ˜0.85μm are desirable (based on the diameters of endotoxins, bacteria, andspores); for these and other applications, a solid material with atleast some larger pores (e.g., less than ˜1, 2, 5, 10, 50, or 100 μm)can be used.

The solid material contains a sufficient amount of surfactant tointerrupt or rupture cell walls of bacteria contacting or coming intothe vicinity of the solid material. The surfactant component(s)generally constitute as low as ˜0.03% and as high as ˜10%, ˜15% or even˜17.5% (all by wt.) of the solid material. The same types of surfaceactive materials discussed previously also can be used in this form.

The surfactant preferably is present in the polymer network at the timethat crosslinking occurs (or the time of polymerization in the case ofthe type of simultaneous polymerization and condensation discussedabove). If it is not, a crosslinked polymer article or film must bepost-treated to ensure proper entrainment of the surfactant. A possiblemethod for accomplishing this is immersion of the article or film in asolution, typically but not always aqueous, that contains one or moresurfactants, followed by removal of excess water via a drying (e.g.,thermal or freeze) or evacuation process. In addition to thesurfactant(s), one or more ionic compounds (salts) can be incorporatedinto the solid material so as to enhance its ability to create localizedregions of high tonicity.

Regardless of how achieved, the local tonicity around the solid materialis at least moderately high, with an osmolarity of at least ˜0.1 Osm/Lbeing preferred for most applications. Solid materials that create localtonicities greater than ˜0.1 Osm/L will have enhanced bactericidalactivity with further increases in the osmotic pressure providingfurther enhanced antimicrobial efficacy.

The solid material can take any of a variety of intermediate and finalshapes or forms including, but are not limited to, a spongy solid thatis permeable to vapor and or liquids; a molded, extruded or depositedsheet; a coating on a surface or layer in a multilayer structure; and anextruded fiber or thread. Once in a particular shape, the material thencan be further processed or manipulated so as to provide a desiredshape, e.g., a sheet good can be rolled or folded so as to provide amembrane of a particular geometry or a larger solid can be ground into apowder.

Both the liquid and solid forms can act at least in part to interrupt orbreak ionic crosslinks in the macromolecular matrix of a biofilm,facilitating the passage of solutes and surfactant through the matrix tobacteria entrained therein and/or protected thereby. Both forms alsotypically do not involve C₁-C₄ alcohols, yet can result, after no morethan 10 minutes residence time, in at least 6 log (99.9999%) reductionsin the number of bacteria in an entrenched biofilm. Embodiments of thecomposition which are non-toxic if ingested can result, after no morethan 10 minutes residence time, in at least 2 log (99%), 3 log (99.9%)or 4 log (99.99%) reductions in the number of bacteria in an entrenchedbiofilm.

In the discussion of particular applications of the previously describedcompositions and solid materials, terms such as “low,” “moderate,” and“high” are used in connection with properties such as toxicity andefficacy. Toxicity refers to negative effects on biological tissues orsystems, with low toxicity referring to little or no irritation evenupon repeated applications, high LD50 values, little or no cytotoxicity,and/or no systemic toxicity, and high toxicity referring to irritationupon repeated exposure, low LD50 values, and/or moderate-to-highcytotoxicity; toxicity generally increases with increasing surfactantconcentration, increasing tonicity, and/or departure of pH from neutral.Efficacy refers to lethality against microbes and/or ability to disruptor even remove the EPS/ECPS in which certain bacterial colonies reside,with low efficacy referring to <2 log, or even <1 log reduction inbacteria (particularly those in an entrenched biofilm) and high efficacyreferring to >2 log, >3 log, >4 log, >5 log and even >6 log reductionsin bacteria; efficacy generally increases with departures of pH fromneutral, surfactant loading increases, tonicity increases, andoptimization of surfactant architecture (e.g., higher charge potentials,smaller groups near a charged site, smaller hydrophilic sites, etc.) ortype (i.e., cationic>zwitterionic>anionic>non-ionic).

Wounds

A number of pathogenic bacteria often are present in and around wounds.Gram positive bacteria include Enterococcus faecalis, Staphylococcusepidermidis, and Staphylococcus aureus. Gram negative bacteria includeKlebsiella pneumonia, Acinetobacter baumanii, Haemophilus influenza,Burkholderia cenocepacia, and Pseudomonas aeruginosa. Various fungi alsocan be present in burn wounds.

Wound colonization often occurs in stages, with bacterial flora in thewound changing over time. Initially, wounds are colonized by aerobicgram positive cocci, such as S. aureus, S. epidermidis, Streptococcusspp., and Enterococcus spp., followed by gram negative rods such as P.aeruginosa, E. coli, K. pneumoniae, and A. baumannii. The wound later iscolonized by anaerobic species such as Prevotella spp., andPorphorymonas spp.

Bacteria can colonize a wound and form a biofilm having mixed speciescommunities of aerobic bacteria near the surface and anaerobic bacteriadeeper in the biofilm. Biofilms are a major, perhaps primary, factor inmaking a wound chronic and preventing healing because neither the body'snatural defenses or antibiotics are able to eradicate bacteria in abiofilm. Additional reasons that wound infections can be difficult totreat include the avascular nature of wound eschars and the presence ofantibiotic resistant microorganisms.

Human and animal wounds can classified as (1) acute, which includes skinabrasions, surgical incisions, trauma, and burns, or (2) chronic, whichincludes diabetic ulcers, pressure ulcers, and venous arterial ulcers.

Acute wounds generally heal through an orderly and timely regenerativeprocess with sequential, yet somewhat overlapping, stages of healing:haemostasis, inflammation, and regeneration and repair.

In haemostasis, damaged endothelial lining exposes platelets tosub-endothelial collagen, which then releases von Willebrand factor andtissue thromboplastin. The von Willebrand factor facilitates plateletadhesion to sub-endothelial collagen and the adhered platelets releaseADP and thromboxane A2, which leads to further platelet aggregation.Tissue thromboplastin then activates the coagulation pathways, leadingto the formation of fibrin, which forms a plug into which platelets andred blood cells are trapped, thereby leading to clot formation.

In inflammation, platelets release platelet-derived growth factor andtransformation growth factor β, which are chemotactic to neutrophils andmonocytes. Neutrophils and macrophages phagocytose foreign material andbacteria.

Platelet-derived growth factor and transformation growth factors aremitogenic to epithelium and fibroblasts. In the regeneration and repairphase, this leads to proliferation of epithelial cells and fibroblasts,which produce collagen. Vascular endothelial growth factor is mitogenicto endothelial cells, and it is released by monocytes in response tohypoxia and promotes angiogenesis.

During the first 24 hours of the healing process in acute wounds,neutrophils are the predominant cell type; this is the acuteinflammation phase where epithelial cells start proliferating andmigrating into the wound cavity. Over the next 24-48 hours, wheremacrophage and fibroblasts are the dominant cell types, epithelial cellproliferation and migration continues and angiogenesis begins.Granulation tissue appears and collagen fibers are present but arevertical and do not bridge the wound gap. Granulation tissue includesnewly formed capillary loops.

By the end of fifth day, the predominant cell type is fibroblasts, whichsynthesize collagen to bridge the wound edges. Epidermal cells continueto divide, the epidermis becomes multilayered, and abundant granulationtissue is present.

During the second week, acute inflammation subsides, and collagencontinues to accumulate.

The foregoing is inapplicable to burns and chronic wounds. In burnwounds, the lack of a protective barrier due to the injury often resultsin septic infections. In chronic wounds, the wound fails to proceedthrough an orderly progression, causing the wound to remain in theinflammation phase of the healing process.

The forms that the treatment can take, the stages of a wound that canbenefit from a treatment, the types and forms of bacteria present in thewound, and the portions of the wound and surrounding skin that can betreated all are indicative of the breadth of the present invention. Eachpossible combination of variables cannot be described individually;instead, many of the variables will be discussed separately, and theordinarily skilled artisan is capable of combining these individualdescriptions to provide for a given form that can be used in or near aparticular type of wound at a particular stage of the healing process.

Wound Types

Both chronic and acute wounds can affect only the epidermis and dermisor can affect tissue down to the fascia.

Chronic wounds, which primarily affect humans although also occur withhorses, most often are caused by poor circulation, neuropathy, and lackof mobility, although other factors such as systemic illness (includinginfection and diabetes), age, repeated trauma and co-morbid ailmentssuch as vasculitis, pyoderma gangrenosum, neoplasia, metabolicdisorders, and diseases that cause ischemia (e.g., chronic fibrosis,atherosclerosis, edema, sickle cell disease, arterialinsufficiency-related illnesses, etc.) or that suppress the immunesystem. All of these can act to overwhelm the body's ability to dealwith wound damage via the common healing process be disrupting theprecise balance between production and degradation of molecules such ascollagen seen in acute wounds, with degradation playing adisproportionately large a role.

Many of the aforementioned causes result in inadequate tissueoxygenation, leading to a higher risk for infection. The immune responseto the presence of bacteria prolongs inflammation and delays healing,leading to a chronic wound and damaged tissue. Bacterial colonizationand infection damage tissue by causing a greater number of neutrophilsto enter the wound site. Although neutrophils fight pathogens, they alsorelease inflammatory cytokines and enzymes that damage cells as well asproduce Reactive Oxygen Species (ROS) to kill bacteria; enzymes and ROSproduced by neutrophils and other leukocytes damage cells and preventcell proliferation and wound closure by damaging DNA, lipids, proteins,the extracellular matrix, and cytokines that facilitate healing.Neutrophils remain in chronic wounds longer than in acute wounds andcontribute to the fact that chronic wounds have higher levels ofinflammatory cytokines and ROS, and chronic wound fluid has an excess ofproteases and ROS, so the fluid itself interferes with healing byinhibiting cell growth and breaking down growth factors and proteins inthe extracellular matrix.

Chronic wounds typically are classified as diabetic ulcers, venousulcers and pressure ulcers, although a small number of wounds notfalling into one these categories can be caused by, for example,radiation poisoning or ischemia.

Generally accepted wisdom is that disinfectants are contraindicated forthe treatment of chronic wounds. This belief is based on a variety offactors, including the potential to damage tissue, potential delay inwound contraction, and general ineffectiveness in the presence oforganic matter, e.g., blood and exudates.

An acute wound results from a force that exceeds the resistive strengthof the skin and/or underlying supporting tissues, resulting in anabrasion, puncture, laceration, or incision. Most acute wounds resultfrom a trauma, with most of the remainder resulting from a medicalprocedure, e.g., surgery. Surgical wounds commonly are classified on asliding scale that ranges from clean to contaminated to dirty, withsurgical wounds that are contaminated or dirty (or known to be infected)occasionally being left open for treatment prior to being sutured.Surgical wounds almost always are dressed, with dressing selection basedon the amount of exudate to be absorbed (leakage of exudate ontosurrounding skin can cause blistering, particularly in the area underthe dressing), supporting haemostasis and protecting against infection.

Wound Treatment

Fundamental wound care protocol involves cleansing (i.e., removal ofdebris and softening of necrotic tissue), possible debridement,absorbing excess exudate, promoting granulation and epithelialization,and treating infection. The cleansing agents used at this stage tend tobe based on surfactants targeted at physical removal of dirt andbacteria with very little (if any) killing of bacteria being effected.

Common treatments for wounds involve dressing changes, medicateddressings, and cleansing or debridement. These often are combined withsystemic and/or topical antibiotics which, unfortunately, areineffective when treating bacteria in a biofilm due to their sessilestate. (Orders of magnitude more antibiotic(s) are needed to killbacteria in a biofilm, an amount which makes most/all antibiotics toxicto the host.)

Changing dressings to dry ones, if performed, can be a means ofmechanical debridement which causes injury to new tissue growth, causespain, predisposes a wound to infection, becomes a foreign body anddelays healing time.

Debridement is performed for necrotic tissue and infection in the wound.This can be accomplished by multiple methods, including mechanical,autolytic, surgical, enzymatic or biochemical, or biological. Hydrogelsare often applied to wounds to keep them hydrated. Negative pressurewound therapy can be used to pull bacteria from a wound. Hyperbaricchambers can also be used to attempt to improve wound healing.

Topical application of an antibacterial product such as alcohols, H₂O₂,povidone-iodine and dilute HClO, sometimes is performed to controlbacterial load. A number of gels and dressing are marketed for thetreatment of infections in wounds, including antibacterial silver-loadedgels, calcium fiber gels and alginates (which entrap bacteria). None ofthese are effective against biofilms, however, and therefore are noteffective in treating many wounds.

As mentioned previously acute wounds generally heal through an orderly,multi-stage regenerative process that includes haemostasis,inflammation, and regeneration/repair. The aforementioned compositionsand solid materials can be useful in treatments at each of these stages.Further, the treatments can be targeted at preventing bacterialcolonization, including the formation of biofilms, or at treating aninfection, including in biofilm form, in or near a wound.

Concurrent with or soon after wound formation, the wound and surroundingskin can be treated so as to minimize the risk of infection. Thistreatment can be effected by cleansing the area with a liquidcomposition or by contacting the area with a solid form carrier such as,for example, a topical wipe. At this stage, long term exposure to thetreating medium is not expected, so increasing efficacy at the cost ofreducing biocompatibility is acceptable.

Efficacy can be bolstered by increasing osmolarity, pushing the pHfarther from neutral and/or using more aggressive surfactants. Forexample, liquid compositions (which includes semi-solid materials suchas gels, salves and balms) intended for immediate removal or topicalwipes intended for use in field situations where other treatment willnot be immediate can have a relatively extreme pH (e.g., 2 to 4 or 10 to12), whereas liquid compositions not intended for immediate removal andtopical wipes intended for use in situations other than extremesituations can have an intermediate pH (e.g., 4 to 5 or 9 to 10), andliquid compositions not intended to be removed, or compositions/wipesintended for use with children or small animals, can have a gentle pH(e.g., 5 to 6.5 or 7.5 to 9).

In addition to or instead of pushing pH farther from neutral, a topicalcomposition also can have a very high osmolarity and/or surfactantloading. Particularly because biofilms are unlikely to have formed atsuch an early stage, the need for H₃O⁺ or OH⁻ ions to assist in breakingup the EPS/ECPS macromolecular matrix might not be as great and,accordingly, higher loadings of other solutes, buffers and/orsurfactants might be sufficient to provide significant lethality againstmany types of bacteria in planktonic form. For example, at this stage ofwound care, a liquid composition with an osmolarity greater than ˜300mOsm/L and a surfactant loading greater than ˜0.075% (by wt.) often canbe adequate for preventing biofilm growth. Adjusting the osmolarityand/or surfactant loading upward (using the amounts provided previously)can provide more effective (i.e., biocidal) compositions, but at thecost of potential for skin irritation.

For biocompatibility reasons, non-ionic and cationic surfactants(particularly benzalkonium chloride and cetylpyridinium chloride) arepreferred.

A variety of grades of liquid antimicrobial compositions for wound carealso are envisioned. For example, various grades of compositions can beprovided based on formulations such as those shown in the followingtable:

TABLE 1 Exemplary wound care compositions A B Acid or base weak acidstrong base Amount of acid/base, g/L  75-150 25-50 Tonicity, Osm/L1.8-2.8 3.0-4.0 Solute trisodium citrate dihydrate NaH₂PO₄ Amount ofsolute, g/L  75-150 25-50 Amount of surfactant, g/L 0.9-1.7 10-20Grades having intermediate properties also are envisioned.

Liquid antimicrobial compositions can be applied directly or can bedelivered and continuously removed, e.g., fed via an instrument like adebrider (e.g., any of the Pulsavac Plus™ family of products,commercially available from Zimmer Inc., Warsaw, Ind.) or even a syringewith a special flow restriction (increased pressure) tip. Also, a liquidcomposition or one of the foregoing additional (solid or semi-solid,particularly gels including those based on any of a variety of PEGs)forms can be used to provide articles with disinfectant properties suchas sponges, topical wipes, bandages, pads, gauze, surgical packing, andthe like.

In addition to being applied to a wounded area to halt or preventmicrobial infection, embodiments of a liquid composition (including gelsand foams) or a topical wipe can be used to disinfect the skin of thosetreating the wound as well as the instruments used in that treatmentincluding, but not limited to, syringes, debriders, tourniquets, and thelike.

Certain types of wounds, patients and/or treatments argue for theinclusion of other types of materials in or with the disinfectingcomposition or material. Non-limiting examples of such materialsinclude, but are not limited to, emollients, lotions, humectants,glycosaminoglycans such as hyaluronic acid, analgesics (e.g., pramoxine,lidocaine, capsaicin, isobutylpropanoicphenolic acid, etc.), colloidalsilver (for treatment of burns) and antimicrobials including sporicides,antifungals, antibiotics (e.g., bacitracin, neomycin, polymyxin B,etc.), fragrances, preservatives (e.g., antioxidants), and the like.

Adding an antihemorrhagic to the disinfecting (antimicrobial)composition or material, or adding the disinfectant to anantihemorrhagic, is potentially quite useful. Examples of commonantihemorrhagic materials used in military and emergency medicalsettings include fibrin, collagen oxidized starch, carboxymethylcellulose, thrombin and chitosan. Various embodiments of thedisinfecting composition or material can be added to an antihemorrhagicmaterial or article such as a haemostatic bandage (HemCon MedicalTechnologies, Inc.; Portland, Oreg.), Tisseel™ fibrin sealant (BaxterInternational Inc.; Deerfield, Ill.), Thrombi-Gel™ gelatin foam hemostat(Pfizer Inc.; New York, N.Y.), GelFoam™ gelatin sponge (Pfizer),GelFoam™ Plus haemostasis kit (Baxter), and the like; alternatively,addition of an antihemorrhagic material to a liquid disinfectingcomposition or to a solid disinfecting material or article also can beuseful. For purpose of exemplification, addition of at least ˜5%, oftenat least ˜10%, commonly at least ˜20% of disinfecting composition ormaterial in solid or semisolid antihemorrhagic materials (e.g., gel-foamand chitosan bandages). Conversely, from ˜1 to ˜80% (by wt.), commonlyfrom ˜3 to ˜70% (by wt.), and typically from ˜5 to ˜60% antihemorrhagicmaterial (with the amount varying primarily based on the identity andefficacy of the antihemorrhagic, e.g., thrombin, chitosan, oxidizedcellulose, or carboxymethyl cellulose) can be added to or incorporatedin a disinfecting composition or material.

Embodiments of the foregoing are expected to find utility in militarybattlefield (e.g., pourable powders carried by field medics) andemergency medical applications (e.g., EMT and ambulance kits as well assurgical theater usages), where disinfecting capability (efficacy)preferably is high, e.g., high osmolarity and surfactant levels. Bloodand wound fluid can hydrate a solid material or a concentrated liquidcomposition, so levels of water or other carrier can be kept low.

Other embodiments are expected to find utility in connection with lesstraumatic wounds, such as shaving cuts or improperly trimmed animalnails, where an embodiment of the liquid or solid disinfecting materialmight be added to a styptic such as alum or TiO₂.

From the foregoing, the ordinarily skilled artisan can envision numerousarticles, techniques and ways in which wounds can be cleansed.

Embodiments of the previously described liquid compositions and solidmaterials also can be used at during various stages of the wound healingprocess.

As described in more detail above, wounds are believed to heal via aprocess that involves haemostasis, inflammation, and repair and/orregeneration. During these phases, a variety of topical medicaments andarticles are applied to wounds and surrounding areas, some for briefperiods of time and others for an extended duration.

For example, many wounds are bandaged soon after occurrence and, incertain circumstances, re-bandaged over time. A bandage that includes anembodiment of the liquid composition can help to prevent infection,treat infection, prevent biofilms, or break up a biofilm and kill thebacteria entrained therein. In this particular form, a strongdisinfecting composition (high osmolarity and relatively extreme pH,e.g., ˜3.5 to 5 or ˜9 to 10.5) can be preferable because high efficacyand microbial toxicity are desired and because the bandage typicallyonly overlays the wound. Methods of making such a bandage includesoaking bandage material in a liquid composition or by coating orentraining in the bandage material a gel, optionally one that undergoesa temperature-based phase change, i.e., becomes less viscous between˜25° to ˜40° C. (Alternatively, some PEG-based gels themselves can actas bandages.) Tailoring the elution rate of the disinfecting compositionover the expected use period of the bandage can be desirable.

Alternatively, an embodiment of a solid form disinfectant can be used toprovide a bandage. The solid article can be in as-made form (e.g.,spongy solid) or in further processed form (e.g., a fiber made from asolid). Here, the bandage material itself is antimicrobial, althoughsuch a material certainly can be further loaded with additionalcomposition or with other antimicrobials.

A variation on the foregoing theme involves surgical packing, which isstructurally similar to a bandage although typically is intended forinsertion into the body for a limited time or to be bioresorbed within apredetermined amount of time. The method of making a surgical packing isessentially the same as those set out above with respect to bandages,although the efficacy and toxicity levels and/or the elution rate can bedownwardly adjusted.

Ongoing wound treatment sometimes involve repeated applications of agel, paste or salve directly to the wound. Because of the amount of timethat such materials are allowed to reside on or in the wound, thesematerials typically involve gentle or only moderately strongdisinfecting composition embodiments. In other words, efficacy andtoxicity can be reduced to avoid pain or tissue damage, a sacrifice thatis offset by the proximity of the treatment to the wound and its lengthof contact.

Both bandages and topical treatments can be used in connection with burnwounds. In such circumstances, addition of a variety of adjuvants andadditional treatments can be preferable. Potentially useful adjuvantsinclude colloidal silver, analgesics, antifungals, emollients,hyaluronic acid, and the like. Because wound edema is common, a somewhatconcentrated, even solid, form of topically applied disinfectant can beused.

Similarly, both bandages and topical treatments can be used inconnection with diabetic and pressure ulcers, i.e., chronic wounds.Similar adjuvants, particularly analgesics, hyaluronic acid, andemollients, can be included in embodiments intended for this use.

Embodiments of the liquid composition also can find utility inconnection with debridement techniques and equipment. Specifically, suchliquid compositions can be used to irrigate or flush an area prior to,simultaneously with, or immediately after debridement.

While most of the foregoing embodiments have been described as singleuse, articles intended for multiple applications are envisioned. Theseare expected to have high loading levels that are intended to elute overtime.

Oral Care

The oral environment initially changes due to an increased concentrationof carbohydrates in the diet of the host. The anaerobic bacteria in theplaque biofilm product acid by fermenting these carbohydrates, thusreducing the pH of the biofilm; some of the more common bacteriaresponsible for this shift in composition include S. mutans, S.sorbrinus, and Lactobacillus casei, all of which can survive at a pHlevel as low as 3.0. As the pH drops, the microflora shift towardsacid-tolerant bacteria, as intolerant bacteria cannot survive in theacidic conditions formed.

At highly acidic pH, the acid-tolerant bacterial biofilm cande-mineralize the tooth enamel, with greater degrees of acidity causingfaster rates of demineralization. (Demineralization of tooth enamel canalso occur solely from the presence of highly acidic substances in theoral cavity.) Caries result if demineralization persists at a rategreater than re-mineralization occurs. S. mutans, Lactobacilli,Lactobacillus acidophilus, Actinomyces viscosus, Nocardia spp., andStreptococcus sanguis are most closely associated with oral caries but,because most plaque-induced oral diseases occur with a diversemicroflora present, the specific causal species is not known.

Plaque and tartar (hardened plaque) become more harmful the longer thatthey remain on the teeth. The bacteria within the biofilm causeinflammation of the gums, commonly known as gingivitis, a mild form ofgum disease that does not include any loss of bone and tissue holdingthe teeth in place. Spirochetes, Actinomyces naeslundii, and P.gingivalis are often associated with the gingivitis.

Untreated gingivitis progresses to inflammation around the tooth,commonly known as periodontitis, a condition where the gums retract fromthe teeth and form gaps or pockets that can become infected because theyare easily colonized by microbes due to dentinal tubules and enamelfissures that lead directly into the gums; the biofilm plaque spreadsand grows below the gum line. The majority of the bacteria within themicroflora in these gum pockets are gram-negative anaerobes, althoughthe identity of the microbes in the biofilm change as the biofilm itselfchanges. At a certain point, the organisms must disperse to otherlocations in the oral cavity to ensure survival.

Periodontitis involves progressive loss of the alveolar bone around theteeth and the connective tissue that holds the teeth in place due to thebacterial toxins in the biofilm and the body's immune response to thebiofilm. If left untreated, this can lead to loosening and subsequentloss of teeth. The areas around and under the gums are difficult toreach via typical oral health care mechanisms that are mechanical innature and, as such, the diseased states of gingivitis or periodontitisoccur. The same bacteria listed above in connection with gingivitis canbe involved in periodontitis, but an enormous variety of other bacteriacan be found in these biofilms.

Peri-implantitis, which is similar to periodontitis but occurs on thesurface of dental implants, refers to the destruction of the supportingperi-implant tissue due to a microbial infection. These infections tendto occur around residual teeth or failing implants, which can act asreservoirs for bacteria and form biofilm colonies, as they have noinherent host response to fight the infecting organisms. The bacterialspecies involved in peri-implantitis are similar to those involved inperiodontitis.

The primary treatment for dental diseases is prevention. For theconsumer, this involves tasks such as tooth brushing (mechanicaldebridement), usually with a fluoride-containing toothpaste; oralrinsing with a mouthwash containing cetylpyridinium chloride, stannousfluoride, or a combination of eucalyptol, menthol, methyl salicylate andthymol in an alcohol vehicle; and flossing. (Mouthwashes and rinses arenot particularly effective at removing plaque, which necessitatescontinued use of floss in the inter-dental regions, as plaque tends toaccumulate in these areas which brushing does not clean.) Regardless,because these preventive treatments are not effective at removing anddisinfecting a biofilm, regular prophylactic treatment (removal ofbiofilm from the teeth, typically by mechanical scraping, althoughlasers have been used additionally or alternatively) by a dentalprofessional usually is necessary.

When dental disease has progressed to periodontitis, mechanical scraping(debridement) has been the only way to remove a biofilm. Professionaltreatment by a dental professional is performed by scaling (scraping oftartar from above and below the gum line) and root planning (removal ofrough spots on the tooth root where the biofilm gathers), sometimes incombination with a laser. In more serious cases, to remove more tartar,flap surgery may be performed, where the gums are lifted so that tartarcan be removed, followed by suturing. Bone and tissue grafts may also beperformed in the area of bone loss.

Medications are sometimes used in conjunction with mechanicaltreatments. These include prescription antimicrobial mouth rinsescontaining chlorhexidine; gum pocket inserts such as an antiseptic chipcontaining chlorhexidine, an antibiotic gel containing doxycycline,antibiotic microspheres containing minocycline, etc.; tablets containingdoxycycline; or even systemic antibiotics.

The aforedescribed antimicrobial compositions, both acidic and caustic,can be incorporated into any of a variety of oral care vehicles such as,but not limited to oral rinses and washes intended for preventive use,oral rinses intended to treat existing dental and gum disease, oralrinse treatment after dental implants, dental implant sterilizationsolutions (pre-surgical), disinfecting solutions for orthodontic devices(e.g., braces, retainers, etc.), irrigation solutions (both for use insurgical procedures, such as root canals and impacted teeth prior toclosure, as well as in general and localized dental procedures), and thelike. The vehicle can be a liquid, gel (e.g., a sealing or packing gelused during and/or after oral surgery), paste (e.g., toothpaste), orsalve (e.g., topical treatment for mouth and lip conditions such ascanker sores) and can be used with components such as fluoride ions andantibiotics, if desired.

Where a liquid antimicrobial composition is to be introduced directlyinto an oral cavity (e.g., a mouthwash or rinse), some preference can begiven to caustic compositions. Because most mouths naturally are asomewhat acidic environment, dental plaque, tartar and other forms ofEPS/ECPS seem to be more impervious or resistant to chelation by acidsthan many other types of biofilm EPS/ECPS. Exemplary pH ranges forcaustic compositions used here range from ˜7.5 to ˜10, commonly from˜7.7 to ˜9.8, more commonly from ˜7.8 to ˜9.7, and typically ˜9±0.5 pHunits. This basicity preferably is achieved with a strong inorganic basesuch as KOH or NaOH.

With respect to tonicity, preferred ranges center around ˜1.75 Osm/L,commonly from ˜1.25 to ˜2.5 Osm/L, more commonly from ˜1.33 to ˜2.25Osm/L, and typically from ˜1.5 to ˜2 Osm/L. To reach this type oftonicity without the pH going outside the previously noted ranges, oneor more ionic compounds can be included in the composition. Exemplarymaterials include, but are not limited to, NaHSO₄, NaH₂PO₄, NaCl, KCl,KI and the like.

Non-ionic and cationic surfactants are preferred for the same reasonsset forth above in connection with wound care. Both benzalkoniumchloride and cetylpyridinium chloride are known to be safe for oralapplications. Exemplary surfactant loading levels range from ˜0.5 to˜1.8 g/L, commonly from ˜0.6 to ˜1.7 g/L, and typically from ˜0.75 to˜1.5 g/L.

The following table provides the composition and properties of anon-limiting example of a liquid antimicrobial composition intended fororal care applications.

TABLE 2 Exemplary oral care composition pH 9.0 ± 0.3 base NaOHadditional solute NaH₂PO₄ tonicity, Osm/L 1750 ± 75  cationicsurfactant(s), g/L 1.1 ± 0.3 additives sweetener, essential oil

The antimicrobial compositions also can be incorporated into solidforms, such as chewing gums, lozenges, denture cleaning tablets, breathmints, removable or dissolving strips, powders and the like. They alsocan be used as, or incorporated in, liquids intended for aerosolizing orother spray techniques, such as breath sprays and dog teeth cleaningsolutions.

For additional information on the type and amounts that can be employedexemplary liquid and solid formulations, as well as methods of making,the interested reader is directed to any of a variety of referencesincluding, for example, U.S. Pat. Publ. Nos. 2005/0169852, 2006/0210491,2007/0166242, 2008/0286213, 2009/0252690, and 2010/0330000. Thosetreatments intended for preventive applications typically will beformulated around lower toxicity thresholds than those intended for useby dental professionals.

Adjuvants that can be included in such treating compositions include,but are not limited to, bleaching agents, binders, flavorings (e.g.,essential oils and artificial sweeteners), humectants, foaming agents,abrasives, desensitizers, tooth whiteners, and analgesics.

Treatment of adenoids and tonsils, although not strictly oral care, alsois possible.

Acute infections of the tonsils and adenoids generally are treated withsystemic antibiotics. If tonsillitis is caused by group A streptococcus,penicillin or amoxicillin are commonly used with some success, whilecephalosporins and macrolides being used less frequently. If these failagainst β lactamase-producing bacteria (which reside in tonsil tissuesand can shield group A streptococcus from penicillin-type antibiotics),clindamycin or amoxicillin-clavulanate may be used.

Group A β-hemolytic streptococcus (GABHS) is the most common reason forchronic tonsil infections. Systemic antibiotics fail to treat GABHS dueto a number of factors, including the presence of β lactamase-producingorganisms that protect GABHS from penicillins, coaggregation with M.catarrhalis, absence of competing bacterial flora, poor penetration ofantibiotics into tonsil cells, etc. Additionally, GABHS is known to formbiofilms. This bacteria, as well as other pathogenic strains, can formbiofilms on and within the tonsils and/or adenoids. Infectious bacteriain biofilm form are relatively impervious to systemic antibiotics,meaning that such high levels of antibiotics are necessary to treat them(i.e., orders of magnitude more than is necessary to kill planktonicbacteria) that the patient is unlikely to survive. Biofilm infectionsoften become chronic.

When the condition becomes chronic, surgical methods are employed toremove the tonsils and adenoids. The current treatment for chronicinfections of the tonsils and adenoids is surgical removal through atonsillectomy and adenoidectomy. This can be done by powered ablationwhich essentially burns away the tonsils and/or adenoids, a techniquethat minimizes or prevents bleeding of the tonsil bed post-surgery, orby cold steel instruments or mechanical debridement, in which caselocalized cauterization is performed on bleeding vessels to preventre-bleeding after surgery. Tonsillectomy, with or without adenoidectomy,is one of the most common surgical procedures in the developed world.These surgical interventions are not without risk, however, withpost-operative bleeding, airway obstruction, and adverse reaction toanesthesia being three of the most common problems. A substantial amountof pain and hospital recovery times also can be associated with theseprocedures. Bleeding can occur when scabs begin sloughing off from thesurgical sites, generally 7 to 11 days after surgery. This occurs at arate of about 1% to 2%, with both risk and severity being higher inadults than in children.

A topical treatment for these infections is not available, as nocommercially available product can disinfect and remove the biofilm andEPS from the tonsil/adenoid surface, nor can these products penetrateinto the tonsil and adenoid surface to treat bacteria within the tissue.Of the oral mouth rinses on the market, which have active ingredientsthat include chlorhexidine, cetylpyridinium chloride, SnF₂ and mixturesof therapeutic oils, none can disinfect a biofilm in the short treatmenttimes available in the oral cavity.

Antimicrobial compositions of the type described above, however, can beeffective in treating infected adenoids and tonsils. A treatment regimenmight be to gargle or rinse with up to 100 mL from 1 to 4 times eachday, with the treatment running for as long as necessary, generally from5-70 days, commonly from 7-65 days, more commonly from 8-60 days, andtypically from 10-50 days, with 30±10 days being envisioned as mosttypical. In addition, direct application of an antimicrobial solidmaterial directly to the affected area(s) also is envisioned.

Advantages of this type of treatment include, but are not limited to,elimination of post-operative bleeding, avoidance of anesthesia,elimination of post-operative pain, preservation of anatomy, eliminationof the risks of morbidity/mortality due to surgery and post-surgicalcomplications, and overall lower healthcare costs.

Medical Equipment

Prior to disinfection or sterilization, all reusable medical devicesmust be cleaned thoroughly, a step that requires that all surfaces,internal and external, be made completely free of so-called bioburden,i.e., residual body tissue and fluids, bacteria, fungi, viruses,proteins, and carbohydrates. After the manual and/or mechanicalcleaning, the devices must be thoroughly rinsed to remove all residualbioburden and detergent. With current technology, if the device is notclean, sterilization cannot be achieved.

Current chemical treatments are ineffective at treating biofilms becauseof their inherent resistance to biocides. Biofilms can be removed byphysical methods such as ultrasound and mechanical cleaning reasonablyeffectively, but ensuring that it occurs correctly and completely eachtime is very difficult.

Endoscopes are particularly susceptible to biofilm formation due totheir use within the body. Removal of biofilm from the internal surfacesof small diameter tubing within endoscopes is difficult due to limitedaccess and the degradation of these surfaces. Biofilm formation withinendoscope channels can result in failure of disinfection procedures andcan create a vicious cycle of growth, disinfection, partial killing orinhibition and regrowth, and patients who undergo endoscopy with abiofilm-containing endoscope are at risk for an endoscopy relatedinfection. Bacteria in a biofilm have been shown to be capable ofsurviving in a down-regulated state after being cleaned and disinfectedby present methods.

The cleaning and disinfecting processes used are dependent upon thetraining and diligence of the operator and, while guidelines forendoscope disinfection have been developed by many organizations, nomethod to determine the efficacy of these regimes on a routine basis iscurrently available. Failure to completely clean and dry an endoscopeusing the current guidelines can lead to biofilm formation, with studiessuggesting that human error is a major contributing factor, along withthe need for rapid turnover of equipment and inadequate training.

Similar problems are inherent in the cleaning and disinfection processesused with other medical devices and equipment, although endoscopes seemto be linked to more outbreaks of HAIs, a problem discussed in moredetail below.

Also problematic are devices and equipment that are not necessarilydesigned for invasive insertion. This includes manual instruments,powered surgical instruments, and even devices cages and guides forperforming spinal surgery. These too are cleaned and disinfectedpost-usage, with the procedure generally involving wiping followed bysterilization (normally by steam, but occasionally by peroxide or otherhigh performance procedures). Some devices are returned to theirmanufacturer for reprocessing, often with steam sterilization bothbefore and after reprocessing.

The formulation of reprocessing cleaning solutions are unique; however,most contain some combination of at least six components: water,detergent, surfactant, buffer, and chelating agents. Enzymes are alsoused to increase cleaning efficacy, speed the cleaning process and helpto minimize the need for manual brushing and scrubbing. A variety ofenzymes, each targeting a particular type of soil, are employed, withthe most common being protease (which helps to break down protein-basedsoils such as blood and feces), amylase (which breaks down starches likethose found in muscle tissue), cellulase (which breaks downcarbohydrates like those found in connective fluid and joint tissue),and lipase (which breaks down fats like those found in adipose tissue).Any combination of these enzymes may be present in a solution. Solutionscontaining enzymes can often be used at a more neutral pH and at lowertemperatures than those without enzymes.

Enzymatic cleaning agents are used as the first step in medical devicedisinfection to remove biofilms. However, physical cleaning with anenzymatic cleaning agent does not disinfect the device. Even a fewviable organisms that might remain after cleaning can accumulate into abiofilm over time. It has been found that commonly used enzymaticcleaners fail to reduce the viable bacterial load or remove thebacterial EPS. Cleaners with high enzyme activity remove some biofilmbut fail to reduce bacterial numbers more than 2 logs (i.e., 99%), andsome enzymatic solutions actually can contribute to the formation ofbiofilms. Accordingly, proper disinfection is required to killdown-regulated microbes and prevents the formation of biofilm.

All devices undergo a disinfection process and users perform a chemicaldisinfection process following cleaning. Either an oxidative oraldehyde-based chemistry is used. However, some disinfection chemistrieshave demonstrated a tendency to promote the formation of biofilms andnone completely remove a biofilm that has already formed. Gluteraldehydesolution buildup over several uses actually has been found to promoteformation of biofilms within the lumens of endoscopes.

Disinfectants employing oxidative chemistries are more effective atcontrolling the formation of biofilms. However, it has been found thateven the harsh environment created by some disinfectants can be survivedby these well-protected microbes, which can survive by using severalfood sources not typically thought to be possible. These disinfectantsare also susceptible to deactivation by proteins that may be present onthe endoscopes and medical devices, especially if the cleaning step isnot adequately performed.

Cleaning chemicals require unimpeded contact with all surfaces of thedevice, internal and external, to assure microbial inactivation; anyresiduals left on the device, including medical soil, contaminants anddetergent residue can interfere with that direct contact. Further, evenif they have access to a biofilm, they cannot kill bacteria entrainedtherein.

The shape and design of some devices and instruments make it impossibleto remove all of the proteins and EPS/ECPS which may be on them.Presently available cleaners or disinfection techniques are unable tocompletely remove EPS/ECPS, especially if there is protein which canprevent cleaning chemicals from reaching these areas. Remaining EPS/ECPScan allow for rapid biofilm reformation on the device, and the EPS/ECPScan be dislodged into the surgical field, including into the patient,allowing for a nidus of infection.

Advantageously, antimicrobial compositions of the type described abovecan be effective in cleaning, disinfecting and sterilizing reusablemedical equipment. In these techniques, both toxicity and efficacy canbe pushed to extremely high levels.

Depending on the nature of the materials from which the equipment ismade, either acidic or basic compositions can be preferred. For example,a caustic composition might be preferred for a metallic piece ofequipment, while an acidic composition might be preferred for a plasticpiece. Extremely acidic or caustic compositions preferably are avoided,i.e., the composition employed commonly has a pH within 4 units,preferably within 3 units, and more preferably within 2 units ofneutral.

Where an acidic composition is employed, a conjugate base of the acidpreferably also is present. Tonicities of solutions employed heregenerally are at least ˜2.0 Osm/L, commonly at least ˜2.5 Osm/L, morecommonly at least ˜3.0 Osm/L, and typically at least ˜3.5 Osm/L. In bothacidic and caustic compositions, additional solute(s) can be present. Incompositions with moderate pH (i.e., 5≦pH≦9, particularly 6≦pH≦8), largeamounts of such solutes can be used; for example, for a composition of6.5≦pH≦7.5, the amount of accompanying salt or solute can be as high as200 g/L, 250 g/L, 300 g/L, 350 g/L, 400 g/L, 450 g/L or even 500 g/L.

Regardless of the nature of the material, cationic surfactants arestrongly preferred, with particular preference being given totetradecyltrimethylammonium halides. Surfactant loading can be pushed tovery high levels, e.g., 10 g/L, 15 g/L, 20 g/L, or even 30 g/L or morecan be used.

Advantageously, the equipment need stay in the composition for no morethan a few hours. For example, in no case should static dwell time berequired to exceed 250 minutes, with less than 200 minutes being common,less than 150 minutes being more common, less than 100 minutes beingeven more common, and less than 50 minutes being typical. Depending onthe particular antimicrobial composition employed, the dwell time canrange from 1 to ˜30 minutes, from ˜2 to ˜25 minutes, from ˜3 to ˜20minutes, or from ˜5 to ˜15 minutes. The amount of dwell time can bedecreased even more with flow for treatment and/or mechanical scrubbingto remove the EPS. Higher-than-ambient temperatures and pressures alsocan increase efficacy, which can be particularly useful equipment havinghigh loadings of bioburden and/or difficult geometry (e.g., scopes).

As an example of the extreme efficacy of the liquid antimicrobialcompositions described herein in this application, a citric acid/sodiumcitrate dihydrate composition having a pH of ˜6.5 and a tonicity of ˜3.5Osm/L and including ˜15 g/L tetradecyltrimethylammonium chloridesurfactant was able to achieve a 9 log reduction (i.e., 99.9999999%) inPseudomonas in small diameter silicone and polyethylene tubing as wellas on metal and plastic coupons.

HAI

Basic routes of infection involve transmission via contact (direct andindirect), droplets, airborne, common vehicle (contaminated items suchas food, water, medications, devices, and equipment), and vector (frommosquitoes, flies, rodents, etc.), with direct contact being the mostfrequent mode.

In direct contact, a colonized person (e.g., a caregiver or anotherpatient) transfers the microorganism from his body to that of asusceptible patient. Indirect transmission involves contact between thehost, usually a caregiver, and a contaminated object which then becomesthe vector for infecting the susceptible patient; examples of objectsthat can become contaminated include instruments and equipment such asneedles, dressings, disposable gloves, saline flush syringes, vials,bags, blood pressure cuffs, stethoscopes, and the like, as well asnon-medical surfaces such as door handles, packaging, mops, linens,pens, keyboards, telephones, bed rails, call buttons, touch plates,seating surfaces, light switches, grab rails, intravenous poles,dispensers, dressing trolleys, countertops, tabletops, and the like.

Droplet transmission occurs when droplets containing microbes from aninfected person are propelled a short distance through the air anddeposited on the patient's body. Droplets may be produced from thesource person by coughing, sneezing, talking, and during the performanceof certain procedures such as bronchoscopy.

Airborne transmission can be by either airborne droplet nuclei ofevaporated droplets containing microorganisms that remain suspended inthe air for long periods of time or dust particles containing theinfectious agent. Microorganisms carried in this manner can be dispersedwidely by air currents and may become inhaled by a susceptible host inthe same room as or quite remote from the original source.Microorganisms commonly transmitted in this manner include Legionella,Mycobacterium tuberculosis and the rubeola and varicella viruses.

Of particular and growing interest and concern are MRSA and VRE.Contamination of the environment with MRSA or VRE occurs when infectedor colonized individuals are present in hospital rooms, often medicalpersonnel carrying the organism in or on their clothing. MRSAcontamination of gloves also has been observed in many personnel who hadno direct contact with the patient but who had touched surfaces ininfected patient's rooms. The hands, gloved or otherwise, of healthcareworkers can become contaminated by touching surfaces in the vicinity ofan infected patient.

In undried form, MRSA can survive for up to 48 hours on a plasticsurface; in dried form, it can survive for several weeks. It is stableat a wide range of temperatures and humidities, and can survive exposureto sunlight and desiccation.

Once a surface becomes contaminated, pathogens can be transferred toother surfaces and patients in the vicinity. Hand washing and gloves canhelp prevent the spread of HAIs via hand-surface transmission but cannoteradicate surface or indwelling contamination, nor do they eliminate thepotential for direct transfer by the patient. However, these methods donothing to treat the presence of these pathogenic bacteria on surfacesand indwelling devices. Touch surfaces commonly found in hospital roomsoften are contaminated with MRSA and VRE, with objects in closestproximity to patients having the highest levels of contamination.

The efficacy of traditional cleaning products (e.g., alcohols,quaternary ammonia compounds, and bleach) to remove surfacecontamination is limited. One recent study of contamination in thehospital environment detected MRSA on 74% of swab samples prior tocleaning and on 66% of swab samples after cleaning, indicating thatcurrent methods for disinfecting hospital surfaces are ineffective.

Some modern sanitizing methods are more effective against selectpathogens; for example, non-flammable alcohol vapor in CO₂ has beendemonstrated to be effective against gastroenteritis, MRSA, andinfluenza, while H₂O₂, as a liquid or vapor, has been shown to reduceinfection rates and risk of acquisition, particularly in connection withendospore-forming bacteria such as Clostridium difficile. However, theseare so-called “contained” methods (i.e., done in a closed, controlledenvironment) and cannot be performed unless the object can be removedand taken to a separate treatment facility, and, even then, none haveproven to be effective against biofilms and, even in those instanceswhen sanitization is achieved, the biofilm EPS is not removed by any ofthese treatments (thereby permitting much more rapid re-growth of thebacterial biofilm as compared to an EPS-free surface when a pathogen isre-introduced).

From the foregoing, the ordinarily skilled artisan can envision manypotential applications for the antimicrobial compositions describedpreviously in the battle against HAIs, as well as biofilms containing orcapable of entraining HAI-causing microorganisms. Common examplesinclude cleaning and/or disinfection of any of the types of hardsurfaces mentioned above, as well as floors and walls; water transportarticles including sinks, therapeutic tubs, showers and drains; beds;transport devices such as gurneys and wheelchairs; surgical suites; andthe like. In these instances, high efficacy and low toxicity generallyare preferred. Particularly preferred are those compositions which willnot harm (e.g., warp or discolor) the surface being treated.

Other common examples include cleaning and/or disinfection of any of thetypes of medical equipment mentioned above, particularly those which areintended for insertion into a patient (e.g., respiratory tubes, IVlines, and catheters) or application to the skin (e.g., stethoscopes,blood pressure cuffs, and the like). Again, high efficacy and lowtoxicity generally are preferred for this type of application.

Other examples include laundering compositions for linens and clothing,hand disinfectants and washes, surgical site preparation solutions, andthe like. Laundering compositions are envisioned as typically beingcaustic and including high loading levels of surfactant, as well asbeing capable of being provided in either liquid or solid form foraddition to wash water. Hand washes and surgical preparationcompositions would be very similar to the OTC and Rx wound washesdescribed previously.

No particular limitation on the types of microbes that can be treatedare envisioned, with particularly problematic pathogenic organisms likeClostridium difficile, Pseudomonas aeruginosa, Candida albicans, MRSA,and VRE being specifically envisioned. Also envisioned is any microbethat forms or can reside in a biofilm, with treatment involving bothdestruction/removal of the biofilm as well as killing of the microbesentrained therein.

Implants

Although terminally sterilized, medical device implants can becomecolonized, prior to and during implantation, with bacteria from theenvironment, from a healthcare worker, or more commonly from bacteriapresent on the patient's own skin. After insertion, implants can becomecolonized from systemic bacteria which make their way to the implantwhich provides a surface for biofilm growth because the implant surfaceis not protected by the host immune defenses.

In addition, currently employed sterilization techniques are notdesigned to remove EPS/ECPS. Therefore, even a sterilized device/articlethat is properly implanted can have EPS/ECPS on its surface fromprevious exposure. The presence of EPS/ECPS greatly facilitatesformation of a biofilm.

Soon after a device or article is implanted, a conditioning layercomposed of host-derived adhesins (including fibrinogen, fibronectin,and collagen) forms on the surface of the implant and invites adherenceof free-floating (planktonic) organisms. Bacterial cell division,recruitment of additional planktonic organisms, and secretion ofbacterial products (such as the glycocalyx) follow, resulting in athree-dimensional structure of biofilm that contains complex communitiesof tightly attached (sessile) bacteria. These bacteria displaycell-to-cell signaling and exist within a polymer matrix containingfluid channels that allow for the flow of nutrients and waste.

Once a biofilm forms on an implant, no currently available treatment caneradicate it. Systemic antibiotics are ineffective against suchinfections, certainly due to the inherent protection by the EPS/ECPS butalso perhaps due to limited blood supply at the surface of the implantedarticle.

Most implants infected by S. aureus or candida require surgical removal.Infections with less virulent coagulase-negative staphylococci may notrequire surgery to remove the implant. If a decision is made to removethe infected implant, complete extraction of all components isperformed, regardless of the type of infecting organism.

An infected joint prosthesis can be retained after debridement or, morecommonly, removed. In removal situations, the affected area is treatedwith large doses of antibiotics, optionally followed by insertion of anew device either immediately or, more commonly, after a 35-45 daycourse of a systemic antibiotic. Infections (and treatments) associatedwith orthopedic devices often result in serious disabilities.

Infections associated with surgical implants are particularly difficultto manage because they require longer periods of antibiotic therapy andrepeated surgical procedures. Mortality attributable to such infectionsis highest among patients with cardiovascular implants, particularlyprosthetic heart valves and aortic grafts.

A biofilm-fouled pacemaker-defibrillator implant often is treated by acombined medical and surgical treatment. Surgical treatment is done intwo-stages: the entire implanted system, including the cardiac leads, iscompletely removed, even in patients with clinical infection of only thepocket, because their cardiac leads may already be colonized (withcardiac rhythm being controlled by a temporary mechanism), a lengthycourse of systemic antibiotics is administered (up to two weeks forinfections of the pulse-generator pocket or 35-45 days forlead-associated endocarditis), and a replacement device/article isimplanted on the contralateral side of the patient.

Infections of fracture-fixation devices that involve bone are treatedwith a 6-week course of systemic antibiotics, whereas 10 to 14 days ofantibiotic therapy are sufficient for superficial infections. Infectionof intramedullary nails is often associated with nonunion of bone andrequires removal of the infected nail, insertion of external-fixationpins, and if necessary, subsequent insertion of a replacement nail.Surgical treatment of infection of external-fixation pins usuallyconsists of a single procedure to remove the infected pins and, if boneunion has not occurred, either insert new pins at a distant site or fusethe bones.

Treatment of infected mammary implants usually entails a two-stagereplacement procedure: removal of the infected implant and debridementof the capsule surrounding it. After administration of a course ofsystemic antibiotics and time for the area to heal somewhat, thecontralateral implant is removed, and a replacement pair of mammaryimplants is inserted.

An infected penile implant typically is removed, and a malleable penileprosthesis is inserted to preserve space. After the necessary systemicantibiotic treatment, a new inflatable implant is inserted in place ofthe malleable prosthesis.

Even cutaneous implants such as tracheotomy tubes, ostomy bags,catheters, and piercings can become fouled with biofilms that aredifficult to remove, a problem exacerbated by the non-removal nature ofcertain types of these articles.

The aforedescribed antimicrobial compositions can be effective topicaltreatments, applied to a to-be-implanted device or article or can beused to wash the infected implant and surrounding tissue to rid the bodyof a biofilm and/or biofilm-forming materials such as EPS/ECPS. Thetypes of surfaces involved can be or include PTFE, PVC, silicone gelsand rubbers, polyethylene, polypropylene, poly(meth)acrylates, stainlesssteel, precious metals (e.g., gold, silver, and platinum), ceramics, andtitanium.

The pocket where the implant is or was located likewise can be treatedwith a liquid composition of the types mentioned above in connectionwith wound care. This can be done at the time of the originalimplantation (i.e., immediately following insertion of the article andprior to suturing), and can be followed with rinsing/irrigation,suctioning or both.

For implants in contact with body tissue, low toxicity butmoderate-to-high efficacy is desired; this might be achievable with acomposition having a fairly neutral pH (e.g., 5≦pH≦9) butmoderate-to-high osmolarity, e.g., at least ˜1.5 Osm/L, commonly atleast ˜1.75 Osm/L, more commonly at least ˜2.0 Osm/L, and typically atleast ˜2.25 Osm/L. Compositions with tonicities of ˜2.5, ˜2.75, ˜3.0,˜3.25, ˜3.5, ˜3.75 or even −4 Osm/L can be used. Cationic surfactantsagain are preferred, preferably at levels of ˜0.5 to ˜2 g/L, morepreferably of ˜0.7 to ˜1.8 g/L, and most preferably of ˜0.8 to ˜1.5 g/L.

For devices not yet in contact with body tissue, the conditions can bemore extreme, i.e., higher toxicity and very high osmolarity. In eithercase, the application of the antimicrobial composition can be byrinsing, wiping, flushing, etc., optionally in conjunction withscraping/debridement and optionally followed by a rinsing step. Inextreme cases, the implanted article can be removed and treated ex vivowith the composition prior to re-implantation.

Alternative or additional techniques involve preparing a body area inwhich an implant is to be inserted by washing, wiping and/or irrigatingthat area with an antimicrobial composition. This can be done inconjunction with surgical preparation sterilization with the same orsimilar composition.

While various embodiments of the present invention have been provided,they are presented by way of example and not limitation. To the extentfeasible, as long as they are not interfering or incompatible, featuresand embodiments described above in isolation can be combined with otherfeatures and embodiments.

That which is claimed is:
 1. A gel useful in reducing bacterialcolonization in or around the area of a wound, said gel comprising atleast one PEG and an aqueous composition having a pH of from 2 to 4, atotal solute concentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7g/L of at least one cationic surfactant, said gel being free ofsporicides, antifungals and antibiotics.
 2. The gel of claim 1 whereinsaid aqueous composition has a total solute concentration of from 1.8 to2.8 Osm/L.
 3. The gel of claim 1 wherein said at least one cationicsurfactant comprises benzalkonium chloride.
 4. The gel of claim 1wherein said at least one cationic surfactant is benzalkonium chloride.5. A gel useful in reducing bacterial colonization in or around the areaof a wound, said gel consisting essentially of at least one PEG, anaqueous composition having a pH of from 2 to 4, a total soluteconcentration of from 1.8 to 4.0 Osm/L, and from 0.9 to 1.7 g/L of atleast one cationic surfactant, and optionally one or more of anemollient, a lotion, a humectant, a glycosaminoglycan, an analgesic,colloidal silver and a coalescent.
 6. The gel of claim 5 wherein saidaqueous composition has a total solute concentration of from 1.8 to 2.8Osm/L.
 7. The gel of claim 5 wherein said at least one cationicsurfactant comprises benzalkonium chloride.
 8. The gel of claim 5wherein said at least one cationic surfactant is benzalkonium chloride.9. A gel useful in reducing bacterial colonization in or around the areaof a wound, said gel comprising: a) at least one PEG and b) acomposition having a pH of from 2 to 4 and a total solute concentrationof from 1.8 to 4.0 Osm/L that consists essentially of (1) water, (2) abuffer system that comprises of one or more organic acids and at leastone salt of one or more organic acids, and (3) from 0.9 to 1.7 g/L of atleast one cationic surfactant, said gel being free of materials havingantimicrobial properties other than those provided by said composition.10. The gel of claim 9 wherein said composition has a total soluteconcentration of from 1.8 to 2.8 Osm/L.
 11. The gel of claim 9 whereinsaid at least one cationic surfactant comprises benzalkonium chloride.12. The gel of claim 9 wherein said at least one cationic surfactant isbenzalkonium chloride.
 13. The gel of claim 9 wherein said one or moreorganic acids comprise at least one polyacid.
 14. The gel of claim 13wherein said at least one polyacid comprises citric acid.
 15. The gel ofclaim 14 wherein said at least one salt of one or more organic acidscomprises a salt of a polyacid.
 16. The gel of claim 9 wherein each ofsaid one or more organic acids is a polyacid.
 17. The gel of claim 9wherein said one or more organic acids is citric acid.
 18. The gel ofclaim 17 wherein said at least one salt comprises a salt of citric acid.19. The gel of claim 9 wherein said at least one salt is a salt ofcitric acid.
 20. The gel of claim 9 wherein said one or more organicacids is acetic acid.